Background: Exposure to intrauterine growth retardation (IUGR) can have a negative impact on nephrogenesis resulting in limited fetal kidney development and supporting the hypothesis that IUGR represents a risk for renal function and long-term renal disease. Cystatin-C (Cys-C), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized; what remains is subsequently eliminated in urine. In tubular diseases and in hyperfiltration conditions, it seems reasonable to postulate that Cys-C degradation would decrease, and consequently an increase in its urinary elimination would be observed. Objectives: The aim of this study was to investigate the urinary excretion of Cys-C simultaneously with the assessment of renal volumes in adequate for gestational age (AGA) and IUGR neonates in order to identify its clinical value in IUGR. Methods: Urinary Cys-C levels were measured using the enzyme immunoassay DetectX® Human Cystatin C kit in IUGR and AGA neonates. Whole renal and renal cortex volumes were assessed with ultrasounds (Vocal II; Software, GE). Results: Urinary Cys-C levels in IUGR were significantly higher than those found in AGA and were negatively correlated to reduced whole renal and renal cortex volumes. Conclusions: The increased levels of Cys-C in the urine of neonates with IUGR were significantly associated with reduced renal/renal cortex volumes, suggesting that Cys-C could be taken as a surrogate of nephron mass. It also could be used as an early biochemical marker to identify IUGR neonates at high risk of developing long-term renal disease and to select patients for monitoring during childhood.

Keywords:
Neonate, Intrauterine growth retardation, Renal volume, Renal cortex volume, Urine, Cystatin-C
1.
Zaffanello M, Brugnara M, Bruno C, Franchi B, Talamini G, Guidi G, Cataldi L, Biban P, Mella R, Fanos V: Renal function and volume of infants born with a very low birth-weight: a preliminary cross-sectional study. Acta Paediatr 2010;99:1192-1198.
2.
Manalich R, Reyes L, Herrera M, Melendi C, Fundora I: Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int 2000;58:770-773.
3.
Hinchliffe SA, Lynch MR, Sargent PH, Howard CV, Van Velzen D: The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol 1992;99:296-301.
4.
Hughson M, Farris AB, Douglas-Denton R, et al: Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 2003;63:2113-2122.
5.
Charlton JR, Springsteen CH, Carmody JB: Nephron number and its determinants in early life: a primer. Pediatr Nephrol 2014;29:2299-2308.
6.
Zohdi V, Sutherland MR, Lim K, Gubhaju L, Zimanyi MA, Black MJ: Low birth weight due to intrauterine growth restriction and/or preterm birth: effects on nephron number and long-term renal health. Int J Nephrol 2012;2012:136942.
7.
Holland P: Placental insufficiency and its effect on the fetus and adult disease. Lancet 1993;341:827.
8.
Myrie SB, McKnight LL, Van Vkiet BN, Bertolo RF: Low birth weight is associated with reduced nephron number and increased blood pressure in adulthood in a novel spontaneous intrauterine growth-restricted model in Yucatan miniature swine. Neonatology 2011;100:380-386.
9.
Vujic A, Kosutic J, Bogdanovic R, Prijic S, Milicic B, Igrutinovic Z: Sonographic assessment of normal kidney dimensions in the first year of life - a study of 992 healthy infants. Pediatr Nephrol 2007;22:1143-1150.
10.
Lim Y, Kim WS, Kim HS, Choi YH, Cheon JE, Shin SM, Kim IO, Choi JH: Ultrasonographic study of initial size and postnatal growth of kidneys in preterm infants. Neonatology 2014;106:107-113.
11.
Cappuccini B, Torlone E, Ferri C, Arnone S, Troiani S, Bini V, Bellomo G, Barboni G, Di Renzo G: Renal echo-3D and microalbuminuria in children of diabetic mothers: a preliminary study. J Dev Orig Health Dis 2013;4:285-289.
12.
Abrahamson M, Olafsson I, Palsdottir A, Ulvsbaeck M, Lundwall A, Grubb A: Structure and expression of the human cystatin C gene. Biochem J 1990;268:287-294.
13.
Finney H, Newman DJ, Price CP: Adult reference ranges for serum cystatin C, creatinine and predicted creatinine clearance. Ann Clin Biochem 2000;37:49-59.
14.
Uchida K, Gotoh A: Measurement of cystatin-C and creatinine in urine. Clin Chim Acta 2002;323:121-128.
15.
Conti M, Moutereau S, Zater M, Lallali K, Durrbach A, Manivet P, Eschwège P, Loric S: Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med 2006;44:288-291.
16.
Koyner JL, Vaidya VS, Bennett MR, et al: Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 2010;5:2154-2165.
17.
Herget-Rosenthal S, van Wijk JA, Brocker-Preuss M, et al: Increased urinary cystatin C reflects structural and functional renal tubular impairment independent of glomerular filtration rate. Clin Biochem 2007;40:946-951.
18.
Cohen J: Statistical Power Analysis for the Behavioral Sciences, ed 2. Hillsdale, Lawrence Erlbaum Associates, 1988.
19.
Fogo AB: Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases. Kidney Int 2000;57:S15-S21.
20.
Saint-Faust M, Boubred F, Simeoni U: Renal development and neonatal adaptation. Am J Perinatol 2014;31:773-780.
21.
Puddu M, Podda MF, Mussap M, Tumbarello R, Fanos V: Early detection of microalbuminuria and hypertension in children of very low birth weight. J Matern Fetal Neonatal Med 2009;22:83-88.
22.
Mitchell EKL, Louey S, Cock ML, Harding R, Black MJ: Nephron endowment and filtration surface area in the kidney after growth restriction of fetal sheep. Pediatr Res 2004;55:769-773.
23.
Boubred F, Saint-Faust M, Buffat C, Ligi I, Grandvuillemin I, Simeoni U: Developmental origins of chronic renal disease: an integrative hypothesis. Int J Nephrol 2013;2013:346067.
24.
Kaseda R, Iino N, Hosojima M, Takeda T, Hosaka K, Kobayashi A, Yamamoto K, Suzuki A, Kasai A, Suzuki Y, Gejyo F, Saito A: Megalin-mediated endocytosis of cystatin C in proximal tubule cells. Biochem Biophys Res Commun 2007;357:1130-1134.
25.
Thielemans N, Lauwerys R, Bernard A: Competition between albumin and low-molecular-weight proteins for renal tubular uptake in experimental nephropathies. Nephron 1994;66:453-458.
26.
Nejat M, Hill JV, Pickering JW, Edelstein CL, Devarajan P, Endre ZH: Albuminuria increases cystatin C excretion: implications for urinary biomarkers. Nephrol Dial Transplant 2012;27:iii96-iii103.
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2016
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